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Neurourology and Urodynamics Mar 2021Abnormal extracellular matrix (ECM) changes are correlated with stress urinary incontinence (SUI). The ECM components versican (Vcan) and hyaluronan (HA) play key roles...
PURPOSE
Abnormal extracellular matrix (ECM) changes are correlated with stress urinary incontinence (SUI). The ECM components versican (Vcan) and hyaluronan (HA) play key roles in regulating tissue inflammation and maintaining connective tissue homeostasis. We analyzed the localization and expression of these ECM components in urethral and vaginal tissues from a rat model of urinary incontinence and from human clinical specimens.
METHODS
Nulliparous rats underwent vaginal distension (VD), a rodent model of SUI, or a sham procedure. Tissues were harvested from six rats per group at days 1, 4, and 21 for immunohistochemistry and RNA expression analysis of ECM components. Periurethral vaginal samples from female patients with SUI were also examined.
RESULTS
High-intensity staining for Vcan was observed 1 day after procedure in both control and VD animals. This level of abundance persisted at day 4 in VD compared to control, with concurrent reduced messenger RNA (mRNA) expression of the Vcan-degrading enzymes ADAMTS5 and ADAMTS9 and reduced staining for the Vcan cleavage epitope DPEAAE. Abundance of HA was not different between VD and control, however mRNA expression of the HA synthase Has2 was significantly reduced in VD tissues at day 4. Abundant Vcan staining was observed in 60% of SUI patient samples, which was strongest in regions of disrupted elastin.
CONCLUSION
Reduction of Vcan-degrading enzymes and HA synthases at day 4 postsurgery indicates a potential delay in ECM turnover associated with SUI. Abundant Vcan is associated with inflammation and elastin fiber network disruption, warranting further investigation to determine its role in SUI pathogenesis.
Topics: Animals; Disease Models, Animal; Extracellular Matrix; Female; Humans; Hyaluronic Acid; Middle Aged; Rats; Rats, Sprague-Dawley; Urethra; Urinary Incontinence, Stress; Vagina
PubMed: 33645869
DOI: 10.1002/nau.24635 -
Aging Feb 2023Gastric cancer is the most common malignant tumor of the digestive system. The progression from gastritis to gastric cancer may be related to genetic factors, but the...
OBJECTIVE
Gastric cancer is the most common malignant tumor of the digestive system. The progression from gastritis to gastric cancer may be related to genetic factors, but the specific molecular mechanism remains unclear. Therefore, an in-depth study of the molecular mechanism of gastritis and gastric cancer is significant.
METHODS
We downloaded two gene profiles, GSE2669 and GSE116312, from the Gene Expression Omnibus (GEO) database. This study aims to apply bioinformatics technology to mine differentially expressed genes (DEGs), DEGs annotation, protein-protein interaction (PPI) network creation, and hub gene identification and expression between gastric cancer patients and gastritis patients. Overall survival analysis of hub genes, analysis by comparative toxicogenomics database for hub genes in gastric cancer, THBS2 and VCAN protein expression by immunohistochemistry for gastric cancer and gastritis as well as design of the biological process (BP) neural network was implemented.
RESULTS
The MSLN, SPP1, THBS2, SPARC, FN1, IGFBP7, VCAN were up-regulated in gastric carcinoma samples, while FGA was down-regulated. The protein expression of THBS2 and VCAN in gastric cancer was significantly higher than that in gastritis. VCAN protein expression was positively associated with tumor invasion ( = 0.011) and HER2 overexpression ( = 0.031). Strong correlation among THBS2, VCAN, and gastric cancer based on the BP neural network.
CONCLUSION
THBS2 and VCAN may be potential targets for improving gastric cancer patients' diagnosis and clinical efficacy.
Topics: Humans; Biomarkers, Tumor; Computational Biology; Gene Expression Profiling; Prognosis; Protein Interaction Maps; Stomach Neoplasms; Versicans
PubMed: 36842141
DOI: 10.18632/aging.204520 -
Heliyon Aug 2023Aberrant expression of long non-coding RNAs (lncRNAs) is associated with progression of multiple human cancers including hepatocellular carcinoma (HCC). However, the...
Aberrant expression of long non-coding RNAs (lncRNAs) is associated with progression of multiple human cancers including hepatocellular carcinoma (HCC). However, the role of lncRNAs in HCC is not been fully understood. Our study aimed to investigate the biological function and potential molecular mechanism of Lnc-PAL2G4A-4 in HCC. In the current study, we show that Lnc-PLA2G4A-4 was significantly up-regulated in HCC tissues and high Lnc-PLA2G4A-4 expression was remarkably associated with tumor size, microvascular invasion and poor prognosis of HCC patients. Functionally, Lnc-PLA2G4A-4 positively regulated cell proliferation, invasion and migration in vitro, and facilitated lung metastasis of HCC in vivo. Mechanistically, Lnc-PLA2G4A-4 functioned as a competing endogenous RNA (ceRNA) to bind to miR-23b-3p and subsequently facilitate miR-23b-3p's target gene versican (VCAN) expression in HCC cells. Over-expression of miR-23b-3p could reverse Lnc-PLA2G4A-4 induced cell phenotypes in HCC and suppress versican expression of by rescue analysis. Collectively, Lnc-PLA2G4A-4 promotes HCC progression by targeting the miR-23b-3p/versican axis, which may be a potential biomarker and therapeutic target for HCC.
PubMed: 37554815
DOI: 10.1016/j.heliyon.2023.e18698 -
The Journal of Histochemistry and... Apr 2018Proteoglycans (PGs) are complex, multifaceted molecules that participate in diverse interactions vital for physiological and pathological processes. As structural... (Review)
Review
Proteoglycans (PGs) are complex, multifaceted molecules that participate in diverse interactions vital for physiological and pathological processes. As structural components, they provide a scaffold for cells and structural organization that helps define tissue architecture. Through interactions with water, PGs enable molecular and cellular movement through tissues. Through selective ionic interactions with growth factors, chemokines, cytokines, and proteases, PGs facilitate the ability of these soluble ligands to regulate intracellular signaling events and to influence the inflammatory response. In addition, recent findings now demonstrate that PGs can activate danger-associated molecular patterns (DAMPs) and other signaling pathways to influence production of many of these soluble ligands, indicating a more direct role for PGs in influencing the immune response and tissue inflammation. This review will focus on PGs that are selectively expressed during lung inflammation and will examine the novel emerging concept of PGs as immunomodulatory regulators of the innate immune responses in lungs.
Topics: Animals; Communicable Diseases; Extracellular Matrix; Humans; Immunity, Innate; Immunomodulation; Lung; Pneumonia; Proteoglycans; Signal Transduction
PubMed: 29328866
DOI: 10.1369/0022155417751880 -
Cancers Oct 2022Proteoglycans (PGs) are pivotal components of extracellular matrices, involved in a variety of processes such as migration, invasion, morphogenesis, differentiation,... (Review)
Review
Proteoglycans (PGs) are pivotal components of extracellular matrices, involved in a variety of processes such as migration, invasion, morphogenesis, differentiation, drug resistance, and epithelial-to-mesenchymal transition (EMT). Cellular plasticity is a crucial intermediate phenotypic state acquired by cancer cells, which can modulate EMT and the generation of cancer stem cells (CSCs). PGs affect cell plasticity, stemness, and EMT, altering the cellular shape and functions. PGs control these functions, either by direct activation of signaling cascades, acting as co-receptors, or through regulation of the availability of biological compounds such as growth factors and cytokines. Differential expression of microRNAs is also associated with the expression of PGs and their interplay is implicated in the fine tuning of cancer cell phenotype and potential. This review summarizes the involvement of PGs in the regulation of EMT and stemness of cancer cells and highlights the molecular mechanisms.
PubMed: 36358747
DOI: 10.3390/cancers14215328 -
Biomolecules Mar 2020Components of the extracellular matrix (ECM) are key players in regulating cellular functions throughout the whole organism. In fact, ECM components not only participate... (Review)
Review
Components of the extracellular matrix (ECM) are key players in regulating cellular functions throughout the whole organism. In fact, ECM components not only participate in tissue organization but also contribute to processes such as cellular maintenance, proliferation, and migration, as well as to support for various signaling pathways. In the central nervous system (CNS), proteoglycans of the lectican family, such as versican, aggrecan, brevican, and neurocan, are important constituents of the ECM. In recent years, members of this family have been found to be involved in the maintenance of CNS homeostasis and to participate directly in processes such as the organization of perineural nets, the regulation of brain plasticity, CNS development, brain injury repair, axonal guidance, and even the altering of synaptic responses. ADAMTSs are a family of "A disintegrin and metalloproteinase with thrombospondin motifs" proteins that have been found to be involved in a multitude of processes through the degradation of lecticans and other proteoglycans. Recently, alterations in ADAMTS expression and activity have been found to be involved in neuronal disorders such as stroke, neurodegeneration, schizophrenia, and even Alzheimer's disease, which in turn may suggest their potential use as therapeutic targets. Herein, we summarize the different roles of ADAMTSs in regulating CNS events through interactions and the degradation of ECM components (more specifically, the lectican family of proteoglycans).
Topics: ADAMTS Proteins; Animals; Axons; Brain; Brain Diseases; Extracellular Matrix; Humans; Proteoglycans
PubMed: 32150898
DOI: 10.3390/biom10030403 -
Reviews in the Neurosciences Nov 2021Chondroitin sulfate (CS) is a kind of linear polysaccharide that is covalently linked to proteins to form proteoglycans. Chondroitin sulfate proteoglycans (CSPGs)... (Review)
Review
Chondroitin sulfate (CS) is a kind of linear polysaccharide that is covalently linked to proteins to form proteoglycans. Chondroitin sulfate proteoglycans (CSPGs) consist of a core protein, with one or more CS chains covalently attached. CSPGs are precisely regulated and they exert a variety of physiological functions by binding to adhesion molecules and growth factors. Widely distributed in the nervous system in human body, CSPGs contribute to the major component of extracellular matrix (ECM), where they play an important role in the development and maturation of the nervous system, as well as in the pathophysiological response to damage to the central nervous system (CNS). While there are more than 30 types of CSPGs, this review covers the roles of the most important ones, including versican, aggrecan, neurocan and NG2 in the pathogenesis of neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis and multiple sclerosis. The updated reports of the treatment of neurodegenerative diseases are involving CSPGs.
Topics: Central Nervous System; Chondroitin Sulfate Proteoglycans; Extracellular Matrix; Humans; Neurodegenerative Diseases
PubMed: 33655733
DOI: 10.1515/revneuro-2020-0146 -
Nature Communications Jul 2017Lean body mass, consisting mostly of skeletal muscle, is important for healthy aging. We performed a genome-wide association study for whole body (20 cohorts of European... (Meta-Analysis)
Meta-Analysis
Lean body mass, consisting mostly of skeletal muscle, is important for healthy aging. We performed a genome-wide association study for whole body (20 cohorts of European ancestry with n = 38,292) and appendicular (arms and legs) lean body mass (n = 28,330) measured using dual energy X-ray absorptiometry or bioelectrical impedance analysis, adjusted for sex, age, height, and fat mass. Twenty-one single-nucleotide polymorphisms were significantly associated with lean body mass either genome wide (p < 5 × 10) or suggestively genome wide (p < 2.3 × 10). Replication in 63,475 (47,227 of European ancestry) individuals from 33 cohorts for whole body lean body mass and in 45,090 (42,360 of European ancestry) subjects from 25 cohorts for appendicular lean body mass was successful for five single-nucleotide polymorphisms in/near HSD17B11, VCAN, ADAMTSL3, IRS1, and FTO for total lean body mass and for three single-nucleotide polymorphisms in/near VCAN, ADAMTSL3, and IRS1 for appendicular lean body mass. Our findings provide new insight into the genetics of lean body mass.Lean body mass is a highly heritable trait and is associated with various health conditions. Here, Kiel and colleagues perform a meta-analysis of genome-wide association studies for whole body lean body mass and find five novel genetic loci to be significantly associated.
Topics: 17-Hydroxysteroid Dehydrogenases; ADAMTS Proteins; Aldehyde Oxidoreductases; Alpha-Ketoglutarate-Dependent Dioxygenase FTO; Body Composition; Extracellular Matrix Proteins; Genome-Wide Association Study; Humans; Insulin Receptor Substrate Proteins; Phenotype; Polymorphism, Single Nucleotide; Quantitative Trait Loci; Regulatory Elements, Transcriptional; Thinness; Versicans
PubMed: 28724990
DOI: 10.1038/s41467-017-00031-7 -
Accumulation of versican facilitates wound healing: Implication of its initial ADAMTS-cleavage site.Matrix Biology : Journal of the... May 2020Versican is a large chondroitin sulfate/dermatan sulfate proteoglycan in the extracellular matrix, and is expressed at high levels in tissues during development and...
Versican is a large chondroitin sulfate/dermatan sulfate proteoglycan in the extracellular matrix, and is expressed at high levels in tissues during development and remodeling in pathological conditions. Its core protein is cleaved at a region close to the N-terminal end of CSβ domain by several members of a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS) family, i.e., ADAMTS-1, 4, 5, 9, 15, and 20. Here, using a CRISPR/Cas9 system, we generated knock-in mice (V1R), which express an ADAMTS cleavage-resistant versican. Some V1R homozygote mice, termed R/R, exhibit syndactyly and organ hemorrhage. In wound healing experiments, R/R wound shows accumulation of versican and activated TGFβ-signaling in the early stage, leading to faster healing than wild type wound. Immunostaining for Ki67, CD31, smooth muscle α-actin, periostin demonstrates higher levels of overall cell proliferation and an increased number of endothelial cells and myofibroblasts. Immunostaining for CD11b and qRT-PCR for macrophage markers revealed increased levels of inflammatory cell infiltration, especially those of M1 macrophages. Cultured R/R dermal fibroblasts revealed increased deposition of versican, type I and III collagens, and hyaluronan, and upregulation of Smad2/3 signaling. Taken together, these results demonstrate that the cleavage site determines versican turnover and that versican plays a central role in the provisional matrix during the wound repair.
Topics: ADAMTS Proteins; Animals; CRISPR-Cas Systems; Cell Proliferation; Cells, Cultured; Extracellular Matrix; Gene Knock-In Techniques; Hemorrhage; Male; Mice; Signal Transduction; Syndactyly; Transforming Growth Factor beta; Versicans; Wound Healing
PubMed: 31669737
DOI: 10.1016/j.matbio.2019.10.006 -
Cell Reports Jun 2020Obesity is characterized by adipose tissue inflammation. Because proteoglycans regulate inflammation, here we investigate their role in adipose tissue inflammation in...
Obesity is characterized by adipose tissue inflammation. Because proteoglycans regulate inflammation, here we investigate their role in adipose tissue inflammation in obesity. We find that adipose tissue versican and biglycan increase in obesity. Versican is produced mainly by adipocytes and biglycan by adipose tissue macrophages. Both proteoglycans are also present in adipose tissue from obese human subjects undergoing gastric bypass surgery. Deletion of adipocyte-specific versican or macrophage-specific biglycan in mice reduces macrophage accumulation and chemokine and cytokine expression, although only adipocyte-specific versican deletion leads to sustained improvement in glucose tolerance. Macrophage-derived biglycan activates inflammatory genes in adipocytes. Versican expression increases in cultured adipocytes exposed to excess glucose, and adipocyte-conditioned medium stimulates inflammation in resident peritoneal macrophages, in part because of a versican breakdown product, versikine. These findings provide insights into the role of adipocyte- and macrophage-derived proteoglycans in adipose tissue inflammation in obesity.
Topics: 3T3-L1 Cells; Adipocytes; Adipose Tissue; Animals; Biglycan; Bone Marrow; Diet, High-Fat; Female; Glucose Tolerance Test; Humans; Hypertrophy; Inflammation; Insulin Resistance; Liver; Macrophages; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Middle Aged; Obesity; Omentum; Organ Specificity; RNA, Messenger; Subcutaneous Fat; Versicans
PubMed: 32610121
DOI: 10.1016/j.celrep.2020.107818